Design, Synthesis, and Evaluation of Novel Quinazolin-4(3H)-One Derivatives: Anti-Leishmanial Activity, Selectivity, and Molecular Docking Insights

Abstract

In this study, 16 novel quinazolin-4(3H)-one derivatives were synthesized and evaluated for their antileishmanial activity against Leishmania major and Leishmania donovani. Among them, compounds 2 (4-hydroxy substituted) and 9 (4-morpholino substituted) exhibited the highest efficacy, with compound 2 showing IC₅₀ values of 23.94 μM for L. major and 90.80 μM for L. donovani, while compound 9 demonstrated IC₅₀ values of 23.05 μM for L. major and 56.30 μM for L. donovani. Miltefosine, the reference drug, showed IC₅₀ values of 32.89 μM for L. major, 4.78 μM for L. donovani, and 7.53 μM for HUVEC cells. Compound 2 showed superior selectivity (SI = 15.2 for L. major and 4.0 for L. donovani) compared to miltefosine (SI = 4.4 for L. major and 0.6 for L. donovani). Molecular docking studies identified phosphodiesterase B1 (PDEB1) as a key target, with compound 2 showing the strongest binding affinity. The docking score of compound 2 was calculated as –11.909 kcal/mol for PDEB1. ADME predictions indicated compound 2's favorable pharmacokinetic profile, including good solubility, permeability, and adherence to Lipinski's Rule of Five. Overall, compound 2 exhibited the most promising therapeutic profile, highlighting its potential as a lead compound for antileishmanial drug development.